Lithium salts have a long history of human consumption beginning in the 1800s. In psychiatry, they have been used to treat mania and as a prophylactic for depression since the mid-20th century (Shorter, 2009). Today, lithium salts are used as a mood stabilizer for the treatment of bipolar disorder, as well as for other psychiatric indications off-label. For example, lithium is the only drug that consistently reduces suicidality in patients with neuropsychiatric disorders (Thies-Flechtner et al., 1996; Goodwin et al., 2003). Despite these effective medicinal uses, current FDA-approved lithium pharmaceutics (lithium carbonate and lithium citrate) are plagued with a narrow therapeutic window that requires regular blood monitoring of plasma lithium levels and blood chemistry by a clinician to mitigate adverse events. Because conventional lithium salts (carbonate and citrate) are eliminated relatively quickly, multiple administrations throughout the day are required to safely reach therapeutic plasma concentrations.
Evidence suggests that lithium may be efficacious for the treatment of Alzheimer's disease. As depicted in FIG. 12, several mechanisms may underlie lithium's potential efficacy for Alzheimer's disease (O'Donnell and Gould, Neurosci Biobehav Rev., 2007; 31(6): 932-962). First, it exerts neuroprotective effects, in part, by increasing brain-derived neurotrophic factor (BDNF). Indeed, chronic lithium treatment has been shown to increase the expression of BDNF in rats (Fukumoto et al., 2001) and humans (Leyhe et al., 2009). This increase in BDNF activity can lead to restoration of learning and memory through promotion of neurogenesis and long-term potentiation (LTP). Another neuroprotective mechanism of lithium is attenuation of the production of inflammatory cytokines like IL-6 and nitric oxide (NO) in activated microglia (Yuskaitis and Jope, 2009). This is particularly important since aberrant microglial function is a common finding in AD (Frick et al., 2013). Lithium has also been found to inhibit certain enzymes in a noncompetitive manner by displacing the required divalent cation, magnesium (Phiel and Klein, 2001). One of these enzymes, glycogen synthase kinase-3 beta (GSK3β), has important implications in Alzheimer's disease. GSK3β was first identified as the molecular target of lithium by Klein and Melton (Klein and Melton, 1996). It is a ubiquitously expressed serine/threonine kinase that is key in the pathogenesis of Alzheimer's disease. The enzyme phosphorylates tau in most serine and threonine residues hyperphosphorylated in the paired helical filaments. Moreover, GSK3 activity contributes both to amyloid-β (Aβ) production and AP-mediated neuronal cell death (Mines et al., J Biol Chem. 2011 Jun. 10; 286(23):20797-811. Aβ is derived from amyloid precursor protein (APP) by sequential proteolysis, catalyzed by the aspartyl protease BACE followed by presenilin-dependent γ-secretase proteolysis (Vasser et al., Science, 1999 Oct. 22; 286(5440):735-41).
It has been demonstrated that therapeutic concentrations of lithium blocked the production of Aβ peptides by interfering with APP cleavage at the γ-secretase step, without inhibition of Notch processing (Phiel C J et al., Nature, 2003 May 22; 423(6938):435-9). Lithium also blocked the accumulation of Aβ in the brains of mice overexpressing APP by inhibition of GSK3α, implicating its requirement for maximal processing of APP (Forlenza O V et al., ACS Chem. Neurosci., 2014, 5 (6), pp 443-450). Since GSK3α also phosphorylates tau protein, inhibition of GSK3α offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles (Phiel C J et al., 2003). In further support, mice with conditional overexpression of GSK3 in forebrain neurons recapitulate aspects of Alzheimer's disease neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, reactive astrocytosis, and spatial learning deficits (Hernandez F et al., J Alzheimers Dis. 2013; 33 Suppl 1:S141-4). Further transgene shutdown in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and amelioration of cognitive deficits, thus further supporting the potential of the GSK3 inhibitor, lithium, for Alzheimer's disease therapeutics. In addition, combined transgenic mice overexpressing GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation develop prefibrillar tau-aggregates (Hernandez F. et al., 2013), which was averted by lithium as well.